Natural Alkaloids: Basic Aspects, Biological Roles, and Future Perspectives

Chinese Journal of

Natural Chinese Journal of Natural Medicines 2014, 12(6): 0401−0406 Medicines

doi: 10.3724/SP.J.1009.2014.00401

Natural alkaloids: basic aspects, biological roles, and future perspectives

QIU Shi, SUN Hui, ZHANG Ai-Hua, XU Hong-Ying, YAN Guang-Li, HAN Ying, WANG Xi-Jun *

National TCM Key Laboratory of Serum Pharmacochemistry, Heilongjiang University of Chinese Medicine, Harbin 150040, China

Available online 20 June 2014

[ABSTRACT] Natural products have gained popularity worldwide for promoting healthcare, as well as disease prevention. Alka- loids are important chemical compounds that serve as a rich reservoir for drug discovery. Several alkaloids isolated from natural herbs exhibit antiproliferation, antibacterial, antiviral, insecticidal, and antimetastatic effects on various types of cancers both in vitro and in vivo. This paper focuses on the naturally-derived alkaloids such as berberine, matrine, piperine, fritillarine, and rhynchophylline, etc., and summarizes the action mechanisms of these compounds. Based on the information in the literature that is summarized in this paper, the use of alkaloids as drugs is very promising, but more research and clinical trials are necessary before final recommendations on specific alkaloids can be made. Following this, it is hoped that as a result of this review, there will be a greater awareness of the excellent promise that natural alkaloids show for use in the therapy of diseases.

[KEY WORDS] Natural product; Alkaloids; Biological roles; Health benefits [CLC Number] R284 [Document code] A [Article ID] 2095-6975(2014)06-0401-06

[1] screening, and discovery platforms . The natural products and Introduction natural products-derived compounds that have undergone clin- Natural products have provided considerable impetus to ical evaluation or registration from 2005 to 2010 by disease the discovery of drugs. In particular, the therapeutic areas of area, i.e. infectious, immunological, cardiovascular, neurologi- infectious diseases and oncology have benefited from nu- cal, inflammatory and related diseases and oncology have been [2] merous drug classes derived from natural product sources. reviewed . As natural products continue to be evaluated for Many new and interesting molecules with biological activity desirable therapeutic activities, significant progress in identify- have been published in the past few years. Recently, natural ing new antibiotics, oncology therapeutics and other useful [3] products from traditional Chinese medicine (TCM) have be- medicines will be made . come important sources for drug discovery. The status of Alkaloids are present in nature primarily as a class of ni- current compound libraries and databases in China are trogen-containing organic compounds in plants, fungi, bacte- large-scale, high-quality, comprehensive, standard, open- ria, and 3 organisms. They possess significant biological ac- access, and are integrated with quality control systems, drug tivities, frequently being one of the important active ingre- dients in Chinese herbal medicine. With advances in the se-

paration of natural products, and the continuing emergence [Received on] 28-July-2013 of new technologies and methods, the development of alkaloid chemistry has expanded. The vast majority of alkaloids [Research funding] This project was supported by the grants from the Key Program of Natural Science Foundation of State (Nos. are present in higher plants, especially in dicots, and a few [4] 90709019, 81173500, 81373930, 81302905, 81102556, 81202639), exist in the lower plants . Alkaloids can be classified by the National Key Technology Research and Development Program of the source combined with chemical structures, like cusco- the Ministry of Science and Technology of China (Nos. hygrine, a pyrrolidine alkaloid derived from ornithine. Leo- 2011BAI03B03, 2011BAI03B06, 2011BAI03B08), and the National nurine is a prominent pharmacologically active guanidine Key Subject of Drug Innovation (No. 2009ZX09502-005). alkaloid, being commonly regarded as the predominant ac- [*Corresponding author] WANG Xi-Jun: Prof., Tel & Fax: tive principle of Leonurus and Leonotis drugs. Its presence 86-451-82110818, E-mail: [email protected] has only been unambiguously proven for the aerial parts of These authors have no conflict of interest to declare. Leonurus japonicus Houtt. [5] Leal et al. found a decreasing

– 401 – QIU Shi, et al. / Chin J Nat Med, 2014, 12(6): 401−406 trend in the discovery of new alkaloids between 2000 and from Chinese herbs such as Coptidis Rhizome. It has been used 2009, contrasting with an increasing number of new ter- for the treatment of diarrhea and other gastrointestinal infec- penoids [6]. Alvarado et al. have reported that a sponge of tions as an antibacterial drug. In recent years, it was reported to the Spongosorites, which contains the nortopsentin and have beneficial effects on the metabolism disorders states of topsentin class of bisindole imidazole alkaloids, exhibits diabetes. The mechanisms of action are diverse, such as regu- [7] potent inhibition of Plasmodium falciparum growth . lating blood cholesterol and triglyceride, lowering blood glu- The evaluation of basic, biological roles, and health benefits cose, ameliorating the insulin resistant state and influencing the arising from the study of alkaloids can provide important function of the pancreatic beta cell [8]. Recently, berberine has information for future pharmaceutical research. In the been reported to possess anticancer activities. Among the vari- present study, the trends associated with the discovery of ous cellular targets of berberine is AMP-activated protein ki- natural alkaloids from a pharmacology and drug efficacy nase (AMPK), which regulates tumor progression and metasta- perspective are discussed. sis. Berberine decreased the migration of SW480 and HCT116 cells, and activated AMPK in human colon cancer cell lines. Background Notably, berberine-induced activation of AMPK, reduced the Berberine integrin β1 protein levels, and decreased the phosphorylation of [9] Berberine (Fig. 1a) is an isoquinoline alkaloid isolated integrin β1 signaling targets .

Fig. 1 Structures of (a) berberine, (b) matrine, (c) verticine, (d) verticinone, and (e) puqietinone Matrine imperialine-3β-D-glucoside, and puqietinone (Fig. 1e), Matrine (Fig. 1b), one of the main active components of purified from Bulbus Fritillariae which is used as an anti- the extracts of the dried roots of Sophora flavescens, has a tussive drug in TCM. A study suggested that the five alka- signficant anti-inflammatory, anti-arrhythmic, and anti- loids could significantly elevate the cAMP concentration fibrotic effects. Furthermore, matrine significantly inhibited in HEK cells transfected with muscarinic M(2) receptor the expression and reduction in the central nervous system of plasmid [14]. Ebeinine and zhebeinine, which were isolated ICAM-1 and VCAM-1, key adhesive molecules and chemo- for the first time from Fritillaria hupehensis, were assayed [10] kines . Li et al found that matrine protects against isoprote- for cytotoxic effects towards the HeLa and HepG2 cell lines. renol-induced myocardial infarction through the eNOS and It showed significant inhibitory effects against both types of asymmetric dimethylarginine pathway [11]. In recent years, ma- tumor cells [15]. Fritillaria thunbergii Miq. has been tradi- trine was also found to have anticancer effects, such as inhibit- tionally used in China as an antitussive and expectorant, and ing proliferation, inducing differentiation and apoptosis in a dose and time-dependent manner, reducing invasion and me- is newly used in the clinical treatment of leukemia. Vertici- tastasis of tumor cell. Matrine could be used as an effective none, a major alkaloid isolated from the bulbs of Fritillaria antitumor agent in therapy of osteosarcoma by targeting the ussuriensis, has been shown to induce differentiation in [16] caspase-dependent signaling pathway [12-13]. human leukemia cells . It may induce apoptosis through Fritillarine the caspase pathway mediated by mitochondrial damage in Verticine (Fig. 1c), verticinone (Fig.1d), imperialine, immortalized keratinocytes and oral cancer cells [17].

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Rhynchophylline ma in mice in a dose-dependent manner [25]. Rhynchophylline (Fig. 2a) is a neuroprotective agent Jatrorrhizine isolated from the Chinese medicinal herb Uncaria rhyncho- Jatrorrhizine (Fig. 2c), a novel tetrahydroisoquinoline al- phylla used in treatment of disorders of the central nervous kaloid, is one of the protoberberine alkaloids derived from the system. Rhynchophylline is beneficial for the treatment of plant Coptis chinensis, has been used for the treatment of a the psychological dependence on amphetamines, as the variety of diseases. It is expected to be developed as a new down regulation of n-methyl-D-aspartate receptor. The ef- gastric prokinetic drug, and its metabolic characteristics in fects of rhynchophylline on the proliferation of PC12 cells humans have been studied. Jatrorrhizine is metabolized by were also investigated [18]. It was demonstrated that rhyn- human CYP1A2 and multiple UGT1A isoforms [26]. Luo et al chophylline suppresses GluA2/3 expression and downregu- suggest that jatrorrhizine protects neuronal-like cells against lates GluN1 expression. Dai et al. had found that phyncho- H2O2-induced toxicity. It also was shown to suppress the ac- phylline might promote the apoptosis of vascular adventitial tivation of caspase-3 induced by Aβ and prevented cytoch- fibroblasts in the thoracic aorta of spontaneously hyperten- rome c transport into the cytosol, demonstrating the neuro- sive rats by regulating the protein expressions of Bcl-2 and protective effects against Aβ-induced injury via the antioxida- Bax. It also can improve the thoracic aorta wall reconstruc- tive potential, which may indicate a therapeutic potential for tion and decrease the tail arterial systolic pressure by atten- Alzheimer's disease [27]. uating the deposition of extracellular matrix [19-20]. Rhyn- Marine alkaloids chophylline and isorhynchophylline may be effective thera- The marine ecosystem and its organisms produce a large peutic candidates for use in the treatment of neurodegenera- group of structurally unique natural products encompassing a tive diseases accompanied by microglial activation [21]. The wide variety of alkaloids, having diverse pharmacological potential molecular mechanism for rhynchophylline or activities. Manzamines are a unique class of β-carboline ma- isorhynchophylline-mediated attenuation was implicated in rine alkaloids with an unusual tetra- or pentacyclic system. the suppression of iNOS protein level, phosphorylation of They have shown a variety of bioactivities against malaria, ERK and p38 MAPKs, and degradation of Iκ Bα. infectious diseases, cancer, and inflammatory diseases. Three new alkaloids, hyrtimomines A-C, were isolated from an Okinawan marine sponge Hyrtios sp. [28]. Hyrtimomines A and B are heteroaromatic alkaloids possessing a fused hex- acyclic ring system, while hyrtimomine C is an alkaloid consist- ing of hydroxyindole and azepino-hydroxyindole moieties. Hyr- timomine A exhibited cytotoxicity against KB and L1210 cells [29]. It is normal that nitrogen-containing pyrroles, indoles, carbolines, tryptamines, tyrosines, and tyramines are excellent platforms for biohalogenation, particularly in the marine en- vironment. Natural organohalogens of all types, especially marine halogenated alkaloids, comprise a rapidly expanding class of natural products, in many cases expressing powerful biological activity [30-31]. Other Alkaloids Vincristine (VCR, Fig. 3a), which is a widely used anti- Fig. 2 Structures of (a) rhynchophylline, (b) piperine, (c) neoplastic drug, was integrated with a submicron-emulsion jatrorrhizine, and (d) marine drug-delivery system to enhance the anticancer effect [32]. A Piperine new aporphine alkaloid, vireakine, along with two known Piper nigrum L. (Piperaceae), black pepper is a very widely alkaloids stephanine and pseudopalmatine, described for the used spice, known for its pungent constituent piperine (Fig. 2b) first time in Stephania rotunda, and five known alkaloids which has been found to have immunomodulatory, anti-oxidant, tetrahydropalmatine (Fig. 3b), xylopinine (Fig. 3c), roemerine anti-asthmatic, anti-carcinogenic, anti-inflammatory, anti-ulcer, (Fig. 3d), cepharanthine (Fig. 3e), and palmatine (Fig. 3f) and anti-amoebic properties [22]. Nirmal et al. have found that were identified. The alkaloids were evaluated for their in vitro the piperine is effective in the treatment of ulcerative colitis antiplasmodial and cytotoxic activities [33]. Chen et al have [23]. Piperine shows a marked improvement in memory, and tested a series of benzylisoquinoline and phenanthrene alka- sensorimotor performance, and reduces the oxidative and loids for their antiplatelet and vasorelaxing actions [34]. Zeph- nitrosative burden [24]. Furthermore, piperine significantly grabetaine has seven cytotoxic activities. A dose dependent reduced venom-induced mast cell degranulation in rats and cytotoxic effect was exhibited by all of the alkaloids on the also significantly inhibited venom-induced lethality, necrosis, cancer cell lines with lycorine (Fig. 3g) and haemanthamine haemorrhage, defibrinogenation and inflammatory paw ede- showing prominent activity [35].

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Fig. 3 Structures of (a) vincristine, (b) tetrahydropalmatine, (c) xylopinine, (d) roemeine, (e) cepharanthine, (f) palmatine, and (g) lycorine duced stereotypy and fighting, and produced a significant fall Biological Roles in the body temperature [41]. Exposure to high altitudes can Antitumor activity cause neurological dysfunction due to decreased oxygen Cancer is a major killer disease all over the world and availability to the brain. A study suggests that huperzine A more than six million new cases are reported every year. Al- supplementation can improve cognitive deficits, reduce oxid- kaloids have played an important role in the development of ative stress, and inhibit the apoptotic cascade induced by [42] several clinically useful anti-cancer agents. The Catharanthus acute hypobaric hypoxia . A research study investigated the alkaloids are established as antimitotic agents, inhibiting the effects of strictosidinic acid isolated from Psychotria myrian- polymerization of tubulin, like vinblastine. Structure-activity tha Müll.-Arg. (Rubiaceae) leaves, on monoamine levels in relationships indicate that electron-withdrawing substituents the rat hippocampus and on monoamine oxidase activity [43]. on the ring contribute to the enhancement of the antitumor Strictosidinic acid seems to act on the 5-HT system in the rat activities [36]. Elamin MH et al have shown that curcumin has hippocampus, possibly inhibiting precursor enzymes of 5-HT cytotoxic effects on medulloblastoma cells, and suppressed biosynthesis. cell proliferation and triggered cell-cycle arrest at G(2)/M Anti-inflammatory effects phase. Furthermore, curcumin inhibited the Shh-Gli1 signal- Oxymatrine is extracted from the traditional Chinese herb ing pathway by down-regulating the Shh protein, and Sophora flavescens Ait., and possesses anti-inflammatory, represents great promise as Shh-targeted therapy for medul- anti-oxidative and anti-apoptotic properties, and has been loblastomas [37]. Berberine could decrease the migration of used for the treatment of chronic viral hepatitis and many SW480 and HCT116 cells. Berberine-induced AMPK activa- other diseases. The effect of oxymatrine on inflammation is tion inhibits the metastatic potential of colon cancer cells by mediated by toll-like receptor4 (TLR4) and nuclear factor decreasing integrin β1 protein levels and downstream signal- kappa-B (NF-κB) oxidative injury. Oxymatrine at 120 mg·kg−1 ing [38]. Rizo et al have tested the cytotoxic activity of the following ICH inhibits inflammatory responses, oxidative indole alkaloids heyneanine, coronaridine, and voacangine injury, and neuronal cell apoptosis [44]. Lee et al. found that against HeLa and B-1 cell lines [39]. Results suggest that fur- lycorine has inhibited LPS-induced production of ther investigation of coronaridine as an antitumor agent has pro-inflammatory mediators, suggesting that lycorine could merit. play an anti-inflammatory role in response to LPS [45]. Ace- Central nervous system effects tylcorynoline, a major alkaloid component derived from Co- Sotoing et al. had examined the alkaloid fraction pre- rydalis bungeana, has the capability to regulate lipopolysac- pared from the leaves of Crassocephalum bauchiense (Hutch.) charide-stimulated activation of mouse bone marrow, which Milne-Redh (Asteraceae) which possessed antipsychotic and are major modulators in the immune system [46]. sedative properties in rodents. It suggested that the alkaloid Antibacterial and antiviral insecticidal effects fraction from C. bauchiense could cause dose-dependent in- A study has showed that the benzo[c]phenanthridine hibition of rearing behavior, decrease the apomorphine- in- alkaloids effectively inhibited the growth of Mycocystis

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Cite this article as: QIU Shi, SUN Hui, ZHANG Ai-Hua, XU Hong-Ying, YAN Guang-Li, HAN Ying, WANG Xi-Jun. Natural alkaloids: basic aspects, biological roles, and future perspectives [J]. Chinese Journal of Natural Medicines, 2014, 12 (6): 401-406

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